Thirty years of investigations into the molecular genetics and signaling of cancer cells have revealed cancer to be a genetic disease. The prevailing carcinogenesis paradigm asserts that cancer originates from a single cell which, through a series of well-defined mutations and selected clonal expansions, ultimately transforms into a cancer cell. Intense study has identified three critical gene classes which contribute to the carcinogenesis process: oncogenes, tumor-suppressor genes and DNA repair genes, sometimes referred to as stability genes. Beyond the abnormal regulation of these classic cancer genes, a number of additional processes which are common across cancer types have been identified as hallmarks of the disease. These include sustained angiogenesis, tissue invasion and metastasis, and unlimited replicative capacity. Cancer cells also exhibit genomic instability, where the progeny of cancer cells express increasing levels of chromosomal aberrations and allelic imbalance. Genomic instability generates the vast genotypic and phenotypic diversity found in all tumors, and it is the major obstacle in cancer treatment.
Despite these major inroads into elucidating the carcinogenesis process, there still remain large gaps in scientists' understanding of how mutations actually drive cell transformation and the subsequent cancer progression. Although gene mutations clearly contribute to cancer, no single mutated gene or combination of mutated genes occur in all or even in the majority of cancers. Moreover, it is not gene mutations, but primarily chromosome-level aberrations that occur in cells following transformation to the cancer state. Although it has long been assumed that cancers arise from mutated differentiated cells, there is now considerable interest in determining if instead it is mutated stem cells that are at the origin of cancer. Stem cells and cancer cells exhibit common properties such as the ability to continuously self-renew and differentiate. Although genomic instability is ubiquitous across cancers, the mechanisms that drive this instability are still undetermined. Inhibition of DNA repair or stability genes, alterations in mitosis genes, aberrant centromeres, aneuploidy, teleomere dysregulations and, for virus-linked cancers, virus-induced fusion of genetically-mutated cells, have all been suggested as causes of the instability. Finally, given that gene mutations and particularly chromosome aberrations decrease the fitness of a cell, it is not understood how cancer cell populations are able to sustain and proliferate in the face of the high degree of chromosomal damage per cell.
Although conventional treatments for neoplasia typically reduce the size of tumors, such responses can be transient. Many cancers will eventually recur, and these recurrences can be fatal. This observation has given rise to the hypothesis that cancer may originate in a small population of cancer stem cells that are responsible for the growth of tumors and that are resistant to conventional cancer therapies. Cancer stem cells are believed to be quite rare, and have been difficult to isolate. Methods for generating cells that are capable of initiating tumors and isolated populations of such cells are required for the identification of novel anti-neoplastic agents that are useful not only as chemotherapeutics, but that can prevent cancer relapse by targeting tumor-initiating cells that are capable of regenerating a tumor when anti-cancer therapy is completed.